A 4-month-old boy is brought to the office for his first visit since arriving in the United States. The patient was recently adopted, and his mother says that he appears tremulous compared to her other children. Over the past week, the patient has also had episodes of upward eye deviation and bilateral arm and leg shaking for approximately 2 minutes at a time. Biologic family history is unavailable. Temperature is 36.7 C (98.1 F), blood pressure is 90/40 mm Hg, pulse is 120/min, and respirations are 30/min. Examination shows a fair-skinned infant with blue eyes and a musty body odor. This patient is most likely to require supplementation with which of the following amino acids?
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This patient's neurologic abnormalities (eg, tremors, seizures) in the setting of musty body odor and light skin/eye color are suggestive of phenylketonuria (PKU), an autosomal recessive disease in which patients have impaired metabolism of phenylalanine, an essential amino acid. PKU is caused by deficiency of phenylalanine hydroxylase, which catalyzes the conversion of phenylalanine to tyrosine.
Most patients with PKU are identified via routine newborn screening (ie, via elevated phenylalanine levels) and treated with a phenylalanine-restricted diet starting in the neonatal period (Choice D). This diet is typically sufficient to prevent manifestations of disease, which are largely due to hyperphenylalaninemia. However, tyrosine is considered an essential amino acid in patients with PKU because it cannot be synthesized from phenylalanine and is required for the production of proteins, catecholamines, and melanin. Therefore, although tyrosine is usually available in a well-varied diet, tyrosine supplementation may be required if intake is insufficient.
Without treatment, hyperphenylalaninemia results in the following findings:
Irreversible neurologic injury: Excess phenylalanine is thought to affect normal neuronal development and increase oxidative stress in the brain, leading to developmental delay, intellectual disability, microcephaly, and seizures.
Reduced melanin production (eg, light skin, blue eyes): Excess levels of phenylalanine inhibit tyrosinase, an enzyme essential in the production of melanin. Low levels of tyrosine also contribute to hypopigmentation in patients who are tyrosine deficient.
Musty odor: Excess phenylalanine metabolites cause malodorous breath, skin, and urine.
(Choice A) Cysteine supplementation may be required in homocystinuria, a condition in which cystathionine synthase deficiency leads to reduced cysteine production and homocysteine and methionine accumulation. Fair complexion and seizures may be seen in infancy; other characteristic features (eg, downward lens dislocation, thrombosis) usually present later. However, musty body odor would not be expected.
(Choices B, C, and F) The branched-chain amino acids (isoleucine, leucine, valine) are elevated in maple syrup urine disease, which is due to branched-chain alpha-ketoacid dehydrogenase deficiency. Buildup of branched-chain amino acids and their metabolites leads to ketonuria (urine with a sweet odor) and encephalopathy within a week of birth; management is dietary restriction of these amino acids.
Educational objective:
Untreated phenylketonuria leads to irreversible neurologic abnormalities (eg, intellectual disability, seizures), as well as reduced melanin production and a musty odor. Pathophysiology involves impaired metabolism of phenylalanine to tyrosine, and treatment includes a phenylalanine-restricted diet that may require supplemental tyrosine.